The present invention relates to the field of ophthalmic drug formulation and delivery. More particularly, this invention relates to an improved method for formulating and administering pharmaceutical drugs which are insoluble or unstable in aqueous solutions.
Biologically active and/or diagnostic agents are conventionally formulated as solutions, suspensions, ointments, or gels (responsive or non-responsive to the ophthalmic environment); or are incorporated into (or absorbed onto) carriers such as solvated polymers, inclusion complexes, microspheres (monolithic or encapsulated), nanospheres, liposomes, ion exchange resins, or combinations of the above. These formulations typically contain water as one of the major components. Unfortunately, not all biologically active agents are chemically stable in an aqueous environment. Many classes of drugs include compounds which are therapeutically effective, but which are hydrolytically unstable. In particular, biologically active ergoline derivatives, such as cabergoline, are highly unstable when placed in an aqueous environment. More generally, prodrugs and soft drugs, which are becoming increasingly important due to improved delivery and targeting, are often subject to hydrolytic degradation, especially on prolonged storage in aqueous environments. In view of the relative instability of such compounds, it is not possible to incorporate these compounds in aqueous solutions, or other types of aqueous compositions which may be stored for relatively long periods (i.e., several months or more) prior to use.
Compounds which are insoluble in water are frequently soluble in hydrocarbon or silicone oils, triglycerides (such as the medium-chain triglycerides commercially available as Miglyols.RTM.), waxes, etc. or in stabilized emulsions (utilizing lipids or surfactants) of these solvents. However, formulations which utilize oils as the vehicle for the active drug are not ideal. This is particularly true with respect to ophthalmic compositions. Among other disadvantages, oils may obscure vision of patients, thereby adversely affecting patient compliance, and high oil/water partition coefficients of compounds may reduce bioavailability.
Various solutions to the above-cited problem have been proposed. One approach has been to use perfluorocarbons as vehicles for delivering drugs to the skin or eyes.
EP-A-0 091 313 describes the use of perfluorocarbons as vehicles for delivering drugs. The perfluorocarbons are utilized in the form of solutions or suspensions. Unfortunately, it has been found that many drugs will not dissolve in perfluorocarbons. It is therefore not possible to form perfluorocarbon solutions containing these compounds.
WO 92/05770 and WO 93/18748 disclose compositions comprising drug carriers (referred to as "drug delivery vehicles" in the references) suspended in nonaqueous liquid vehicles (referred to as "carriers" in the references). The nonaqueous liquid vehicles are perfluorocarbons or fluorinated silicones. The perfluorocarbons useful in the reference compositions include perfluorocyclocarbons, acyclic perfluorocarbons and their derivatives. These references also disclose that the perfluorocarbon derivatives are typically nitrogen and oxygen containing compounds such as amines and ethers. The nonaqueous liquid vehicles, however, are preferably perfluorinated, meaning that all of the hydrogens bonded to carbons of the vehicle compounds are substituted with fluorine.
Solutions are generally preferable to suspensions for drug delivery. This is particularly true in the field of ophthalmic drug delivery. Thus, there is need for improved solution vehicles to deliver drugs which are unstable or insoluble in aqueous media.
Accordingly, it is a principal object of the present invention to provide pharmaceutical solutions for delivering water-labile, biologically active drugs through a wide variety of acceptable routes of drug administration. It is a further object of the present invention to provide pharmaceutical compositions containing biologically active drugs which exhibit improved shelf life and stability.
It is an additional object of the present invention to provide pharmaceutical compositions which release the dissolved drug effectively at the desired site of action.
A further object of the present invention is to provide ophthalmic compositions which are comfortable, non-toxic, transparent, non-irritating, odorless, and do not cause blurring of vision when administered to the eye.